The human gut microbiota contains more than 100 trillion
bacteria that, under normal physiological conditions, have beneficial
symbiotic interactions with the host. However, a growing body
of evidence has shown that alternations in the composition
and diversity of the gut microbiota, or dysbiosis, can influence
the development and progress of metabolic and neurological
disorders. Communication between the microbiota and the brain
is a bidirectional system involving endocrine, metabolic (bacterial
components and metabolites), immune, and neural pathways. Gut
microbiota composition influences the signals transmitted from the
gut to the brain. Alternatively, the brain utilizes similar mechanisms,
in particular endocrine and neural signaling, to modulate the
composition of the gut bacteria. In this review, we describe the
recent evidence of gut microbiota interaction with the central
nervous system to influence physiological and cognitive functions
and the therapeutic potential of modulation of the gut microbiota
composition.

Keywords: Gut microbiota; Gut-brain axis; Dysbiosis

Gut Microbiota Composition

The human microbiota contains as many as 100 trillion
bacteria and there are 10 times more bacterial cells in our body
than human cells [1]. Specific bacterial phyla reside in the different
body habitats; Actinobacteria, Firmicutes and Proteobacteria for
skin, Bacteroidetes, Firmicutes, Fusobacteria and Proteobacteria
for the oral cavity, Bacteroidetes, Firmicutes, and Proteobacteria
for the airway tract, Firmicutes for the urogenital tract and
Bacteroidetes and Firmicutes for the gastrointestinal (GI) tract
[2]. In the human GI tract, microbiota distribution is not spatially
even; bacterial presence and diversity increase along the GI tract
[3,4]. The gut microbiota is primarily composed of anaerobic
bacteria; more than 90% of them belong to the Bacteroidetes and
Firmicutes phyla with minor proportions of other phyla, including
Proteobacteria [5].

Alteration in Microbiota Composition or Dysbiosis

Under normal physiological conditions the gut microbiota and
its host have beneficial symbiotic interactions. The microbiota
notably plays essential roles in the protection against epithelial cell injury [6], metabolic regulation [7], GI tract development
[8], innate and adaptive immune responses, and absorption
of nutrients [9,10]. Alterations in microbiota composition
and dysregulation of the intestinal mucosa homeostasis
have been implicated in the development and progression of
pathologies. This compositional change in the microbiota and/
or an abnormality in the interactions between the host and the
commensal microbiota is referred to as dysbiosis. Gut microbiota
dysbiosis has been linked to chronic low-grade intestinal
inflammation and acute intestinal autoimmunity diseases such as
Irritable Bowel Syndrome (IBS) and Inflammatory Bowel Disease
(IBD) [11,12]. Abnormal microbiota composition is associated
with a wide range of metabolic and behavioral disorders, such as
anxiety/depression [13-15], autism spectrum disorders [16-18],
hepatic encephalopathy [19], multiple sclerosis [20, 21], allergies
[22], visceral pain [23,24], atherosclerosis [25] and cardiovascular
risks [26]. GI microbiota dysbiosis might also be involved in the
development and persistence of systemic disorders [27]. For
example, obesity has been characterized by a decrease in overall
diversity [28] and an increase in Proteobacteria abundance and
in the Firmicutes to Bacteroidetes ratio [28,29] and microbiota
composition is believed to influence energy balance and glucose
homeostasis [30-32].

Evidence that changes in microbiota composition are
correlated with metabolic and behavioral disorders has
drawn attention to a potential causal role for the microbiota in
pathologies and has led to the emergence of the ‘microbiota-gutbrain
axis’ concept [33-35]. The gut–brain axis is a bidirectional
communication system between the GI tract and the brain [36]
via hormonal, immunological, and neural signaling. Information
from the GI tract and the intestinal microbiota can reach the
peripheral and Central Nervous System (CNS), concurrently
the brain is able to influence GI functions such as motility and
secretion but also immune responses and cytokine production
[36,37].

The Microbiota-Gut-Brain Axis

The gut microbiota can modulate gut-brain axis signaling
via direct and indirect mechanisms. The microbiota acts via
endocrine, metabolic (bacterial components and metabolites), immune, and neural (vagal afferents and Enteric Nervous System
(ENS)) pathways to modulate brain functions. For example, in a
recent study by Duca et al, it was shown that the colonization of
germ-free (GF) mice with obesity-prone microbiota remarkably
increased the expressions of pro-inflammatory factors
interleukin (IL)-6, TNF-α, and Toll-Like Receptor 4 (TLR4) in the
hypothalamus. In addition, colonization treatment affected the
expressions of hypothalamic energy-regulating neuropeptides;
reducing Proopiomelanocortin (POMC) and increasing Agouti-
Related Peptide (AgRP) and Neuro Peptide Y (NPY) expressions.
The brain uses the same mechanisms to modulate the composition
of the gut bacteria. For instance, under stressful conditions, the
hypothalamus–pituitary–adrenal axis regulates the secretion
of cortisol, which can have both local and systemic effects on
immune cells secretion, including cytokines. Cortisol release can
alter gut permeability and intestinal barrier functions, eventually
leading to changes in gut microbiota composition [38,39].

Communication between the gut and the brain notably
involves endocrine signaling. Enteroendocrine cells release gut
peptides in response to enteric stimuli [40,41]. For example,
cholecystokinin and gastrin are released in response to feeding
to regulate appetite [42]. Enteroendocrine cells located in the
epithelial lining possess specialized microvilli that project into
the lumen. Consequently, these cells come into close contact with
gut microbiota, enabling functional communication. In several
studies, the gut microbiota was shown to influence the number
of enteroendocrine cells and the release of gut peptides [43].
Cani et al. investigated the effect of prebiotic modulation of gut
microbiota on intestinal permeability in leptin deficient (ob/
ob) mice by assessing changes in the microbial composition,
intestinal permeability, gut peptides, and hepatic and systemic
inflammation. The mice treated with the prebiotic carbohydrates
(fermentable oligofructose) showed decreased endotoxemia
and hepatic inflammation as well as improved intestinal
barrier function and tight junction integrity. These effects were
associated with increases in the endogenous Glucagon-Like
Peptide-2 (GLP-2) production and are believed to be GLP-2-
dependent [44]. Moreover, colonization of GF animals with either
a "lean" or an “obese” microbiota leads to replication of the donor
phenotype [45,46]. GF rodents colonized with an obese–type
microbiota notably exhibit a decrease in GI peptide expression,
such as Glucagon-Like Peptide-1 (GLP-1) and Peptide YY (PYY)
[46]. Changes in gut peptide secretion could modulate gut-tobrain
neural signaling. Information between the gut and the
brain is conveyed via the ENS. Vagal afferent neurons are notably
in charge of transmitting sensory information from the GI tract to
the CNS. Vagal signaling has been extensively studied in relation
to feeding behavior and control of appetite; signals originating
from the GI tract are conveyed via the vagus nerve to the Nucleus
of Solitary Tract (NTS) in the brainstem and hypothalamus to
regulate ingestive behavior [47]. Microbiota-induced changes
in gut peptide expression have notably been associated with
alterations in food intake [46].

While microbiota-driven changes in gut peptide secretion
can affect gut-brain neural communication, there is evidence of a potential direct effect of bacteria on sensory pathways.
Recent work has found that bacteria are able to produce
neurotransmitters; bacterial colonization of GF mice resulted
in over 2-fold increase in 5-hydroxytryptamine (5-HT) [48].
Specifically, commensal Lactobacilli and Bifidobacteria have
been shown to produce γ-aminobutyric acid (GABA) [49] while
Escherichia spp., Bacillus spp. and Saccharomyces spp. produce
noradrenaline; Candida spp., Streptococcus spp., Escherichia
spp., and Enterococcus spp. can produce 5-HT. Additionally,
Bacillus spp. and Lactobacillus spp. can produce dopamine
and acetylcholine, respectively [49,50]. There is growing
evidence that vagal signaling is involved in microbiota-tobrain
communication. Chronic treatment with L. rhamnosus in
mice induced region-dependent changes of GABA expression
in the brain and attenuated stress-related disorders, including
anxiety and depression. However, these effects were blunted
in vagotomized mice [13]. Similarly, Bercik et al. demonstrated
that the anti-anxiety effect of B. longum involves vagal afferent
signaling. Using a chemically induced colitis mouse model, they
found that B. longum stabilized the anxiety-like behavior but the
effect was absent in mice that were vagotomized. They proposed
that anxiolytic effect of B. longum was attributed to its signaling
to the CNS by activation of the vagal system at the level of the
ENS [51].

The Role of Microbiota-Derived Metabolites

GI bacteria may modulate endocrine and neural signaling
indirectly via release of metabolites and/or bacterial compounds.
Short Chain Fatty Acids (SCFA) are produced by bacterial
fermentation of non-digestible dietary polysaccharides; notably
acetate, propionate, and butyrate [52] and have profound impacts
on gut health [53-55]. Butyrate is the preferred source of energy
for colonocytes over propionate, acetate, or glucose [52] and is also
involved in cell proliferation and differentiation. Sodium butyrate
has notably been shown in vivo to have preventive effects on
colon cancer development [52]. Importantly, nutrient deficiency
in the colon characterized by the absence of SCFA is associated
with colitis, underlying the potential role of SCFA in regulating
local inflammation [52]. SCFA are rapidly absorbed within the
colon leading to an increase in pH in the distal colon, affecting
mineral absorption, notably enhancing sodium absorption and
calcium bioavailability [52]. Acetate and propionate are absorbed
into portal circulation [56]. Acetate as a component of acetyl-CoA
is believed to increase plasma cholesterol by contributing to
cholesterol synthesis while propionate may decrease cholesterol
levels by inhibiting acetate to acetyl-CoA conversion [57]. The
decrease in the acetic acid-to-propionic acid ratio was suggested
as a possible indicator of the hypolipidemic effect of prebiotics
(inulin and fructooligosaccharides) [58]. Moreover, recent
studies have demonstrated that SCFA act as endogenous ligands
for two G protein-coupled receptors, free fatty acid receptor
2 (FFAR2) and 3 (FFAR3). They are expressed in the GI tract,
liver, immunocytes, and adipocytes [59-61]. Acetate infusion in
mice induced a decrease in circulating free fatty acids which was
blunted in the FFAR2-knockout mice [62], suggesting that acetate
acts via FFAR2 to control circulating free fatty acid levels and lipolysis. In addition, SCFA may also influence the regulation of
feeding. Leptin expression is increased by SCFA infusion, leading
to a decrease in food intake, but this effect was almost abolished
by knockdown of FFAR3 [63]. Moreover, FFAR2 and FFAR3
activation has been shown to be involved in the production and
release of gut peptides GLP-1 and PYY, resulting in decreased
food intake [64, 65].

Additionally, we have recently demonstrated that
Lipopolysaccharides (LPS), endotoxins from Gram-negative
bacteria, affect vagal signaling to promote food intake [66].
Obesity is associated with chronic increase of circulating LPS,
quoted as metabolic endotoxemia [67]. We have used miniosmotic
pumps to mimic metabolic endotoxemia and found that
infusion of low dose of LPS was sufficient to alter vagal afferent
neuron protein levels, impairing leptin signaling and promoting
overfeeding [66]. Known probiotics, such as Bifidobacterium
spp. have been shown to improve mucosal barrier function and
reduce endotoxin levels; these changes are associated with a
reduction in energy intake [68].

Bacterial metabolites, notably bacterial fermentation
products such as lactic and propionic acids, not only modulate
host physiology but can impact behavior. Levels of lactic acid in the
cecal contents were strongly associated with occurrence of anxiety
and memory loss in rats fed a high fermentable carbohydrate diet
[69]. Human studies also suggest a link between fermentation
products and behavior. High fecal concentrations of propionic
acid correlate with anxiety in patients with IBS [70]. Additionally,
increased availability of substrates for microbial fermentation,
such as carbohydrate maldigestion or malabsorption, has been
shown to be associated with depression in female subjects [71].

Amino acids are also degraded by gut bacteria, notably
tryptophan [72], a precursor of 5-HT [73]. A growing body of
evidence indicates an association between the dysregulated
kynurenine arm of tryptophan metabolism and many CNS
and GI disorders [74]. Kynurenine is a product of tryptophan
metabolism and has neuroactive and anxiogenic characteristics
[75]. Conversely, another product of the tryptophan breakdown,
kynurenic acid is considered to be neuroprotective. Indeed,
reduced kynurenic acid to kynurenine ratio has been found
in the major psychiatric disorders such as depression and
schizophrenia [76]. Compositional shift in gut microbiota and
subsequent alterations in serum levels of kynurenine could result
in modifications of behavior and CNS response. For instance,
the administration of a probiotic, L. johnsonii to diabetes-prone
BioBreeding rats resulted in a decrease in serum kynurenine
level [77]. Conversely, GF mouse colonization increased
circulating levels of kynurenine and decreased expression of
genes associated with neuronal development and function [78].
Taken together, these data suggest that metabolic products of
gut microbiota could be involved in the modulation of the host’s
brain functions and behavior.

Expression of other genes involved in behavior has been
shown to be under the influence of microbiota, notably Brain
Derived Neurotropic Factor (BDNF). BDNF regulates multiple aspects of cognitive and emotional behaviors and its expression
can be modulated by prebiotic supplementation. BDNF gene
expression notably increased in rats when orally administrated
with prebiotics, fructooligosaccharides and galactooligosaccharides
for five weeks [79].

Immunological Mechanisms

Microbiota composition has direct effects on the host immune
system at the levels of both innate and adaptive immunity [80,81].
First, the innate immune system is capable of sensing various
types of bacterial components via Pattern Recognition Receptors
(PRRs). PRRs recognize bacterial products like LPS, lipoproteins,
and peptidoglycans and trigger the appropriate responses, such
as the release of pro-inflammatory cytokines [82]. There are two
types of PRRs, Toll-like receptors (TLRs) and Nod-like receptors
(NLRs) [83,84]. TLRs are notably expressed on enterocytes and
enteric neurons, including vagal afferent neurons [66,85-87].
TLR activation leads to activation of transcription factors, such
as Nuclear Factor Kappa B (NFκB) to promote pro-inflammatory
cytokine synthesis and secretion [88]. NOD activation also
contributes to the onset of inflammatory responses and insulin
resistance [89].

Additionally, a growing body of evidence shows that the gut
microbiota coordinates T cell differentiation, enabling the full
functioning of the acquired immune system. γδ intraepithelial
lymphocytes play a crucial role as inhibitors of bacterial
penetration during intestinal injury [90]. γδ T-helper (Th) cell
differentiation can be regulated by the commensal microbiota. The
microbiota is involved in generating adenosine 5’ triphosphate,
which then activates a subset of dendritic cells and contributes
to Th17 differentiation [91]. Specifically, differentiation of Th17
cells in the lamina propria of the small intestine is correlated with
the presence of bacteria from the Cytophaga-Flavobacterium-
Bacteroides group [92]. Additionally, the stimulation of TLR5,
mediated by flagellin, triggers the expression of IL-6, inducing
Th17 cell programming [93]. Moreover, polysaccharide A from B.
fragilis can protect from inflammatory diseases such as colitis by
suppressing pro-inflammatory IL-17-producing CD4+ T cells and
inducing IL-10-producing CD4+ T cells [94].

The crucial role of the microbiota in host immunity has been
demonstrated with GF animal models. GF mice display defective
gut-associated lymphoid tissues, the first class of intestinal
defense, less cellular lamina propria, smaller and less mesenteric
lymph nodes [95,96], and a reduced number of intraepithelial
lymphocytes compared to the colonized animals [97,98]. They
also showed decreased expressions of TLRs and class II major
histocompatibility complex proteins, which act as pathogen
sensors and antigen presenters, respectively [99,100]. Normal
activation of TLRs appears to be critical not only for appropriate
immune signaling, but also for host physiology. For example, TLR5
mainly recognizes bacterial flagellin [101] and TLR5-knockout
mice exhibited profound metabolic disturbances manifested as
obesity, dyslipidemia, hypertension, and insulin resistance [102].

As the proper maintenance of the gut microbiota contributes
to both immunological and metabolic balances [103], dysbiosis may result in the dysregulation of both systems [104]. Indeed,
over-activation of PRRs induced by the intestinal microbial
alterations and the resulting low-grade inflammation seem to
play a crucial role in the development of obesity. Recent work
focusing on bacterial LPS has demonstrated that metabolic
endotoxemia and the subsequent activation of TLR4 are involved
in the development of type 2 diabetes and cardiovascular diseases
by contributing to low-grade inflammation and disrupting energy
regulation [66,105,106]. Chronic LPS injections in animal models
are sufficient to induce weight gain and insulin resistance,
pointing to a potential causal role for bacterial products and
altered immune response in obesity and related metabolic
disturbances [66,67].

Pro-inflammatory cytokines, such as IL-4, have been reported
to be associated with a series of psychiatric disorders [111].
In addition, Desbonnet et al. have studied in rats the effect
of probiotics on anxiety behaviors associated with maternal
separation and have found that administration of probiotics
B. infantis 35624 decreased IL-6 secretion and improved
depression-like behavior in pups [109].

Descending Signals from the Brain Can Modulate
Microbiota Composition

The gut-brain axis is a bidirectional communication route. For
example, vagal efferent neurons send motor information from
the brain to the periphery [112] and central signaling can affect
gut microbiota composition to modulate host physiology. The
brain-gut microbiota axis is mediated via endocrine and neural
pathways in both direct and indirect manners [38,113,114].

Central modulation of satiety plays a crucial role in the braingut
microbiota pathway. The CNS is involved in controlling food
intake and food preferences and resulting changes in nutrient
availability for gut microbiota can lead to alteration of microbial
composition. In addition, central neuropeptides such as POMC
or GLP-1 are involved not only in regulating hunger and satiety,
but also in GI secretion and motility [115]. This downward
regulation is mediated via the vagal efferent neurons, notably
for GI motility [113]. Changes in GI transit have been shown to
modify microbiota composition [116]. In mice, administration of
polyethylene glycol decreases gastrointestinal transit time and
is associated with changes in microbiota composition, notably
a decrease in the relative abundance of families Peptococcaceae,
Eubacteriaceae, and Anaeroplasmataceae and an increase in
families Bacteroidaceae and Peptostreptococcaceae. Similar
changes can be induced via dietary manipulation of gastric
motility [116]. Altered profile of gut microbiota has been linked
to diseases such as IBD, which are associated with changes in GI
motility [117].

The Hypothalamus–Pituitary–Adrenal (HPA) axis is known to mediate stress and anxiety responses that can influence intestinal
metabolism, including gut motility and secretion, leading to
environmental changes for gut microbiota [38]. A recent study
demonstrated that social disruption, as a source of stress,
caused dramatic changes in the gut microbiota composition
in adult mice. Mice subjected to stress exhibited an increase in
Clostridium spp. and a decrease in Bacteroides spp. The alteration
in microbial composition was followed by increased levels of
circulating inflammatory cytokines such as IL-6 and Monocyte
Chemoattractant Protein 1 (MCP1) and caused increased
bacterial translocation [118]. In their previous study, the authors
also showed that the secondary lymphoid organs were involved
in the stress-induced increase in bacterial translocation [119]. In
rats, stress has also been shown to disrupt GI epithelial barrier
integrity, leading to mast cell activation in the mucosa [120].
Moreover, it has been shown that early life exposure to stress,
such as maternal separation, is associated with increased levels
of corticosterone and immune response and altered microbiota
in rat feces. These changes were associated with significant
increases in the pro-inflammatory cytokines TNF-α, IL-6, and
Interferon-γ (IFN-γ) [121]. This is particularly interesting as
recent work has established that early perturbations in GI
microbiota are persistent in adulthood [122]. While the pathways
linking stress to microbiota composition remain unclear, there is
evidence of direct neural communication between the host and
its microbiota. The QseCsensor kinase, a bacterial adrenergic
receptor, has recently been identified as a microbial receptor for
epinephrine and norepinephrine directly originating from the
host [114].

Microbiota Modulation as Therapeutic Strategies
against Dysbiosis

Alterations in microbiota composition lead to changes in
endocrine, neural, and immune signals from the GI tract and
this information is then conveyed to the CNS [38]. Alternatively,
central signals can modulate GI functions and microbiota
composition [27]. Therefore, in a dysbiotic state, this bidirectional
communication can lead to a worsening of the situation and
several strategies have been developed to stop or attenuate
this potential vicious circle. A growing body of evidence shows
that alternations in the composition and diversity of the gut
microbiota have a substantial influence on the pathophysiology
of metabolic and CNS disorders, and consequently there has been
a growing attention to microbiota manipulation.

Probiotics

One approach is the use of probiotics. “Probiotics are
live microorganisms which when administered in adequate
amounts confer health benefits on the host” [123]. Among
several mechanisms for actions of probiotics, probiotics exhibit
beneficial effects on the host through the modulation of the
intestinal microbial composition by suppressing pathogenic
bacteria such as clostridia and increasing or protecting beneficial
populations such as bifidobacteria [124]. Probiotics inhibit
growth of enteric pathogens by direct antimicrobial actions via
production of inhibitory substances, immunomodulation via immune cell stimulation, competitive exclusion via blocking
of epithelial binding receptors, and improvement of epithelial
barrier integrity via mucin and defensins [125,126].

Probiotics can exert a direct antimicrobial ability by
producing inhibitory substances such as organic acids and
bacteriocins, peptides with a potent antibacterial property
[127,128]. Lactobacillus and Bifidobacterium spp. exhibited antiinfective
effects against enterohemorrhagic E. coli O157:H7 in
human intestinal cells by producing lactic acid and subsequently
decreasing luminal pH [129,130]. Additionally, Corr et al.
demonstrated that L. Salivarius UCC118 protected mice from the
invasive foodborne pathogen L. monocytogenes via stimulation of
bacteriocins [130].
Probiotic bacteria can also act as immunomodulatory
agents to alleviate the inflammatory response to infection in
the host GI tract [131,132]. They can substantially reduce proinflammatory
cytokine secretions such as TNF-ɑ and IFN-γ,
while stimulating anti-inflammatory cytokines such as IL-10 and
TGF-β [131,133,134]. B. breve and S. thermophilus have been
shown to produce metabolites which inhibit TNF-ɑ secretion
from peripheral blood mononuclear cells [131,133-135]. Some
probiotic strains induce secretory Immunoglobulin A (IgA)
production, leading to activation of regulatory T (Treg) and
dendritic cells [136]. For example, the oral administration of
L. casei to BALB/c mice induced activation of the gut mucosal
immune system by increasing the level of IgA+ cells [137].

Some probiotic bacteria can compete with pathogens for
binding sites to the mucous layer or epithelial cells, inhibiting
the effect of pathogenic bacteria on epithelial cells [138,139].
Surface-layer proteins are located outside the bacterial cell wall
and are involved in tissue adherence. In a study using human
epithelial (HEp-2 and T84) cells, surface-layer protein extracts
from L. helveticus blocked the adherence of E. coli O157:H7 to
epithelial cells [140].

In addition, probiotics are capable of improving epithelial
barrier integrity by inducing the expression of mucin from the
host [141]. Mucin, as the primary component of the mucosal layer
in the GI tract, protects the intestinal epithelium from pathogenic
invasion by forming a defensive physicochemical barrier [142]. In
an in vitro study using the Caco-2 cell line, L. casei GG was shown to
induce MUC2 expression, inhibiting bacterial translocation to the
intestinal epithelium [141]. Some probiotics can also stimulate
the release of defensins, which play a role in stabilization of
epithelial barrier function as antimicrobial peptides [143].
Several probiotic strains were found to strengthen intestinal
barrier function in the Caco-2 cell line by up-regulating the
expression of human β-defensin 2 through induction of mitogenactivated
protein kinases. They include B. longum, B. infantis,
B. breve, L. acidophilus, L. casei, L. delbrueckii ssp. bulgaricus, L.
plantarum, and Streptococcus salivarius ssp. thermophilus [144].

Experimental and clinical studies have found that probiotics
have therapeutic effects on metabolic diseases. For example, the
administration of dual probiotic strains (L. curvatus HY7601
and L. plantarum KY1032) to diet-induced obese mice led to not
only reduced body weight gain and fat accumulation in adipose
tissue, but also decreased levels of plasma insulin, leptin, and
total cholesterol [145]. Pro-inflammatory genes (including
TNF-α, IL-6, IL1β and MCP1) were down-regulated in adipose
tissue and fatty acid oxidation-related genes were up-regulated
in the liver [145]. The reduction of cytokine expressions in
probiotic-treated mice may be explained by a decreased release
of pro-inflammatory LPS [146]. As mentioned before [141-
144], probiotic bacteria improve intestinal barrier integrity,
thereby decreasing LPS translocation to the periphery and
leading to reduced production of pro-inflammatory cytokines
in adipose tissue. Similarly, it has been recently established
that L. rhamnosus GG (LGG) displays anti-obesity and antidiabetic
effects when administered to high-fat diet-fed mice
[147,148]. Oral administration with LGG for 13 weeks notably
led to increased expression of fatty acid oxidation genes in the
liver and decreased expression of gluconeogenic genes. LGG
treatment also increased glucose transporter-4 gene expression
in skeletal muscle and adiponectin production in adipose tissue
[147,148]. In a clinical setting, B. infantis 35624 was orally
administrated for 6 to 8 weeks to patients with gastrointestinal
(ulcerative colitis) or non-gastrointestinal (chronic fatigue
syndrome, psoriasis) disorders [149]. The results showed that
levels of plasma C - Reactive Protein (CRP) and pro-inflammatory
cytokines (TNF-ɑ and IL-6) were significantly reduced in three
inflammatory disorders compared with placebo. Furthermore, B.
infantis 35624 significantly decreased LPS-stimulated secretion
of TNF-α and IL-6 in B. infantis 35624-treated healthy subjects
compared with the placebo group. Thus, it was concluded that
the beneficial effects of B. infantis 35624 are applicable both
locally (gastrointestinal) and systemically [149].

In addition to physiological effects, there is evidence
suggesting that the use of probiotics can be applied to the
treatment of psychiatric conditions [150]. The beneficial effects of
probiotics on psychopathological disturbances may be explained
by reduction in pro-inflammatory cytokines, competitive
exclusion of pathogenic bacteria, and interaction with the CNS,
resulting in changes in levels or functions of neurotransmitters
[151-154]. The findings of the possible association of anxiety
or depression with elevated levels of pro-inflammatory factors
(TNF-α, IL-6, and CRP) indicate the involvement of inflammatory
factors in psychological conditions [155]. Cytokine receptors
located on peripheral nerves, including the vagal nerve, may
convey inflammatory signaling to the brain, which possibly
evokes psychologically unstable states such as anxiety and
depression [156]. Several studies have demonstrated that
Lactobacillus and Bifidobacterium strains alleviate inflammatory
responses in rodents [108,157,158]. Desbonnet et al. found that
the administration of probiotics B. infantis for 14 days improved
depression-like behavior in rats with a significant attenuation
in pro-inflammatory cytokines IFN-γ, TNF-ɑ, and IL-6 [108].
Additionally, in rats subjected chronically to the forced swim
test, B. infantis administration triggered a significant increase
in plasma tryptophan concentration, known as a serotonergic
precursor [108]. Another probiotic, L. paracasei, has been shown
to produce neurotransmitter GABA [159]. In addition, probiotics can also exert anti-stress effects by decreasing the level of
cortisol, a well-characterized stress hormone [160]. For example,
a study investigating potential synergic effects of L. helveticus
and B. longum administration showed that probiotic treatment
attenuated anxiety- and depression-related behaviors as well as
levels of serum cortisol in both rats and human subjects [161].

Taken together, these data show that certain probiotic
strains can modulate various aspects of metabolic and behavioral
functions. However, further experimental and clinical trials
are required to identify the exact mechanisms and pathways
mobilized by probiotics.

Prebiotics

In addition to probiotics, modulation of gut microbiota
composition can be mediated with prebiotics. Prebiotics are
“non-digestible food ingredients that beneficially affect the
host by selectively stimulating the growth or activity of one of a
limited number of bacterial species, thus improving host health”
[162]. Chronic administration of prebiotics such as oligofructose
to genetic (ob/ob) or diet-induced obese and diabetic mice
increases the expression of intestinal proglucagon and circulating
GLP-1, improves glucose homeostasis and leptin sensitivity, and
decreases oxidative stress, low-grade inflammation, and fatmass
accumulation [163]. These metabolic improvements are
associated with compositional shift of specific gut microbiota
phyla, specifically, decreased Firmicutes and increased
Bacteroidetes [119]. Additionally, administration of oligofructose
restores A. muciniphilia abundance, which is associated with
improved metabolic states [164]. Similarly, oligofructose
administered to diet-induced obese rats reduces fat mass and
weight gain with a noticeable increase in bifidobacteria and
lactobacilli [165]. Importantly, oligofructose supplementation
has been shown to promote weight loss in overweight and
obese humans as well [166]. Another prebiotic, honey, a natural
oligosaccharide-rich product, is shown to improve glycemic
control in streptozotocin-induced diabetic rats [167]. It is
believed that pancreatic β-cells are vulnerable to oxidative stress
due to the relatively low levels of antioxidant enzymes in the
pancreas, which may play a crucial role in the β-cell deterioration
frequently characterized in diabetes [168,169]. In rat models
with diabetes, honey supplementation was shown to decrease
oxidative stress in the pancreas [170]. In addition to affecting
metabolic outcomes, the daily use of prebiotics for three weeks
in humans has been shown to reduce the cortisol stress response
and improve emotional processing [171].

Fecal Microbiota Transplant (FMT)

FMT refers to “the process of instilling a liquid suspension
of stool from a healthy donor into the patient’s upper
gastrointestinal tract through a nasogastric/nasoduodenal
catheter or gastroscopy, or into the colon through a colonoscopy
or a rectal catheter” [172]. It has been used for more than 50 years
primarily for the treatment of C. difficile infection, but recently,
there has been a growing interest in utilizing this bacteriotherapy
for metabolic syndrome [173]. In related trials, FMT recipients
showed more diversity and more similarity to the donor in composition of the fecal microbiota after transplantation with an
increased proportion of Bacteroidetes and decreased proportion
of Proteobacteria [5]. Moreover, Vrieze et al. have reported
that insulin sensitivity of recipients with metabolic syndrome
increased 6 weeks after infusion of intestinal microbiota from
lean donors [173]. The therapeutic effects of FMT also can be
applicable to other disorders, such as Parkinson’s disease [174],
chronic fatigue syndrome [175], and childhood regressive autism
[176].

Bariatric Surgery

Bariatric surgery (weight loss surgery) is the most effective
treatment for morbid obesity and is considered when other
attempts have failed. The procedure facilitates a marked weight
loss and improves metabolic parameters, including insulin
sensitivity, pancreatic β-cell function, and inflammatory status
as well as cardiovascular risk factors [177,178]. Reduced food
reservoir and malabsorption have been suggested as possible
mechanisms underlying the health-promoting influences of
bariatric surgery, but a growing body of evidence suggests a
beneficial role of altered gut microbiota profile following the
surgery [179]. Indeed, certain procedures such as the Roux-en-Y
Gastric Bypass [RYGB] have been reported in humans and animals
to cause a marked increase in Gammaproteobacteria, decrease
in Firmicutes, and loss of methanogen bacteria [179], which
are associated with metabolic improvements after treatment
[180,181]. The RYGB surgery in rats with normal weight caused
a decrease in Firmicutes with significantly higher proportion
of Proteobacteria compared to the control rats treated with
sham operation [182]. Additionally, abundance of the butyrateproducing
F. Prausnitzii species, considered to reduce low-grade
inflammation, was increased following RYGB in the study.

Conclusion

A growing body of experimental and clinical evidence shows
the potential involvement of the gut microbiota with metabolic
and neuropsychiatric disorders and has drawn attention to the
concept of ‘microbiota-gut-brain axis’. The gut microbiota can
modulate gut-brain axis signaling via endocrine, metabolic,
immune and neural mechanisms.

Similarly, the same pathways are used by the brain to
modulate the composition of the intestinal microbiota. However,
in a dysbiotic state, this bidirectional communication can
lead to the pathophysiological progress of metabolic and CNS
disorders, and consequently there has been a growing attention
to microbiome-based therapeutics, ranging from probiotics,
prebiotics, fecal microbiota transplant to bariatric surgery. Still,
there are unknowns regarding the role of the gut microbiota in
metabolic and CNS disorders to be addressed prior to further
development of new therapeutics. First, we need specific
identification of potential mechanisms or pathways by which
microbiota manipulation can affect the host physiology and
psychology. Second, it is crucial to clarify the influence of maternal
gut microbiota and infant nutrition on the microbial development
in early childhood and throughout adulthood. Third, the impact
of variation in the gut microbiota needs to be elucidated on drug metabolism, bioavailability, and toxicity as well as on microbiotagut-
brain communication. This could be approached with the use
of GF animals and ones colonized with existing microbial strains
to determine the effect of specific bacteria on host physiology and
related therapeutic strategies. Overall, further understanding of
the interaction of the microbiota-gut-brain axis with the host’s
metabolism will guarantee more successful and promising
improvements in the treatment of metabolic and CNS diseases.